Abstract
Disruption of skin homeostasis can lead to inflammatory cutaneous diseases resulting from the dysregulated interplay between epithelial keratinocytes and immune cells. Interleukin (IL)-22 signaling through membrane-bound IL-22 receptor 1 (IL-22R1) is crucial to maintain cutaneous epithelial integrity, and its malfunction mediates deleterious skin inflammation. While IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling, how IL-22BP controls epithelial functionality to prevent skin inflammation remains unclear. Here, we describe the pivotal role of IL-22BP in mediating epithelial autoregulation of IL-22 signaling for the control of cutaneous pathogenesis. Unlike prominent expression of IL-22BP in dendritic cells in lymphoid tissues, epidermal keratinocytes predominantly expressed IL-22BP in the skin in the steady state, whereas its expression decreased during the development of psoriatic inflammation. Deficiency in IL-22BP aggravates psoriasiform dermatitis, accompanied by abnormal hyperproliferation of keratinocytes and excessive cutaneous inflammation as well as enhanced dermal infiltration of granulocytes and γδT cells. Furthermore, IL-22BP abrogates the functional alternations of keratinocytes upon stimulation with IL-22. On the other hand, treatment with IL-22BP alleviates the severity of cutaneous pathology and inflammation in psoriatic mice. Thus, the fine-tuning of IL-22 signaling through autocrine IL-22BP production in keratinocytes is instrumental in the maintenance of skin homeostasis.
Highlights
The maintenance of structural and immunological barrier func tion in the skin is a prerequisite for limiting exposure to potentially harmful environmental substances and preventing systemic dissemination and entry of commensal and pathogenic microorganisms [1, 2]
Similar to the published reports [5, 6], high transcriptional expressions of Il22 and Il22ra2 were found in peripheral lymph nodes (PLNs) and mesenteric lymph nodes (MLNs), as well as colon and Payer’s patch (PP) (Figures S1A,B in Supplementary Material), and CD11chighI-A/I-E+ conventional dendritic cells (cDCs) showed a higher expression of the Il22ra2 transcript than other leukocytes in both PLNs and MLNs, but not in the spleen (Spl) (Figures S1C–E in Supplementary Material)
To confirm that cutaneous epithelial cells, but not CD11chighIA/I-E+ cDCs, act as the main producer of IL-22 binding protein (IL-22BP), we examined the transcriptional expression of Il22ra2 in the absence of cDCs using CD11c-diphtheria toxin (DT) receptor (DTR)/enhanced green fluorescent protein (EGFP) transgenic (Tg) mice [26], in which CD11chighEGFP+ cDCs were depleted after a single DT injection
Summary
The maintenance of structural and immunological barrier func tion in the skin is a prerequisite for limiting exposure to potentially harmful environmental substances and preventing systemic dissemination and entry of commensal and pathogenic microorganisms [1, 2]. In contrast to the ubiquitous expression of IL-10R2 on immune cells, the expression of IL-22R1 is restricted to nonhematopoietic cells at body barriers including epithelial cells of the lung and gastrointestinal tract and keratinocytes in the skin, thereby allowing IL-22 to be an important cytokine mediating the crosstalk between leukocytes and epithelia at barrier surfaces [4,5,6]. As the main physiological function of IL-22 includes a reinforcement of epithelium barrier function through induction of antimicrobial peptides (AMPs) to promote antimicrobial immunity [7], and wound healing through induction of epithelial cell proliferation and survival following tissue damage in pathophysiological conditions [8,9,10], it appears to have an important role in the maintenance of epithelial integrity at barrier surfaces [11, 12]. The fine-tuning of IL-22 signaling is implicated to be required to maintain epithelial integrity and control cutaneous tissue inflammation and immunosurveillance, as well as normal skin wound healing
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